calcineurin inhibitor-free, steroid-free immunosuppressive regimen in simultaneous islet-kidney transplantation for uremic type 1 diabetic patients

Conditions: Islets of Langerhans Transplantation; Diabetes Mellitus, Type 1; Kidney Transplantation

Summary: the investigators hypothesize that a calcineurin inhibitor-free, steroid-free, co-stimulatory blockade-based immunosuppressive regimen, in combination with a glp-1 agonist, will reduce the islet mass required to achieve and sustain insulin independence following simultaneous islet-kidney transplantation.

this is a single center, open-label, non-randomized, prospective, pilot study of 8 type 1 diabetic/uremic patients, ages 18-60 undergoing simultaneous islet-kidney transplantation. study to include both male and/or female subjects. we hypothesize that a calcineurin inhibitor-free, steroid-free, co-stimulatory blockade-based immunosuppressive regimen, in combination with a glp-1 agonist, will reduce the islet mass required to achieve and sustain insulin independence following simultaneous islet-kidney transplantation. furthermore, we anticipate an improvement in creatinine clearance and a reduction in interstitial fibrosis/tubular atrophy in the transplanted renal allograft, and a reduction of "de novo" human anti-hla antibody and auto-antibody formation against the respective donors. without calcineurin inhibitors or steroids, we hypothesize that belatacept, in conjunction with sirolimus and mycophenolic acid will provide balanced immunosuppression for combined islet-kidney transplantation.

Eligibility criteria:
inclusion criteria: * subjects will include those with type 1 diabetes mellitus, undergoing kidney transplantation, and: * are closely followed by a primary care provider and/or endocrinologist for \>6 months prior to enrollment in the trial * do not have psychogenic factors which preclude therapeutic compliance * have a fasting c-peptide of \ 5 years • are between 18 and 65 years of age * have a creatinine clearance of less than 20 ml/min * have a body mass index of less than or equal to 28 * in the case of women of childbearing potential (wocbp), must have a negative pregnancy test and avoid pregnancy throughout the study and 8 weeks after final dose of study drug. * wocbp must use two adequate methods of contraception. * a male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study and for up to 8 weeks after the last dose of study drug to minimize the risk of pregnancy. exclusion criteria: * untreated proliferative diabetic retinopathy * hgba1c \>12 * creatinine clearance \> 20 ml/minute * presence of panel reactive antibodies (pra) \>20% (per cdc-based assay) * malignancy or previous malignancy, except for adequately treated skin cancers (basal cell or squamous cell carcinoma) within the past 5 years * sensitivity to iodine and/or shellfish (re: iothalamate-based gfr testing) * x-ray evidence of pulmonary infection * active infections * active peptic ulcer disease, gall stones, hemangioma, cirrhosis or portal hypertension * serological evidence of hiv, hbsag or hcv * abnormal liver function tests (elevated ast and alt \> 2x upper limit of normal) * anemia (hemoglobin) \<9 gm/dl * serum triglycerides \>200 mg/dl * serum cholesterol \>240 mg/dl * body mass index above 28 * unstable cardiovascular status (including positive stress echocardiography if \>age 35); severe coexisting cardiac disease, myocardial infarction within the 6 months prior to enrollment in the study, left ventricular ejection fraction of \<30%, or evidence of ongoing ischemia * prostate specific antigen (psa) \>4 in males \>40 years old or with family history of prostate cancer * pregnancy or breastfeeding * sexually-active females who are not: a) post-menopausal, b) surgically sterile, or c) not using an acceptable method of contraception (oral contraceptives, norplant, depo-provera, and barrier devices are acceptable; condoms used alone are not acceptable) * alcohol abuse, substance abuse or smoking within the previous 6 months * insulin requirement \>1.5 u/kg/day * negative for epstein-barr virus by igg determination * history of factor v deficiency * acute or chronic pancreatitis * recurrent attenuated vaccine(s) within the previous 2 months * use of an investigational agent within the past 4 weeks * sexually active, fertile men not using effective birth control, if their partners are wocbp * prisoners, or subjects who are involuntarily incarcerated * subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness * previous kidney transplant or previous non-renal transplant * kidney transplant from expanded criteria donor (ecd) * kidney cold ischemic time projected to be \> 20 hours * currently receiving immunosuppressive agents for autoimmune disease or other conditions or have comorbidities that treatment with such agents are likely during the trial * any condition or circumstance that makes it unsafe to undergo an islet cell or kidney transplant